Low-dose Tamoxifen in Hodgkin Lymphoma Survivors for Breast Cancer Risk Reduction Mantle radiation has been a cornerstone of HL treatment; however, female survivors of HL treated with mantle irradiation before age 30 have a 20- to 55-fold increased risk of developing breast cancer (BC) - a risk that is comparable to that of BRCA mutation carrierrs Surgical prophylaxis is very effective in reducing the risk of BC, but such invasive strategies are not suitable for all women. Pharmacologic interventions exist, but only tamoxifen is approved for use in young women who have not yet reached menopause. Standard-dose tamoxifen (20 mg daily) is associated with undesirable side effects, but recent studies have laid convincing groundwork that tamoxifen at lower doses may be similarly efficacious in reducing BC risk with fewer side effects. We hypothesize that tamoxifen administered at a lower dose (5 mg daily) would be both an efficacious and safe non-surgical risk reduction intervention for female adult survivors of HL diagnosed during childhood or as a young adult. Thus, using a Phase IIb randomized, double-blind, placebo-controlled trial of low-dose tamoxifen (5 mg daily) in long-term female HL survivors treated with chest radiation, we aim to 1) Determine the impact of a two-year course of low-dose tamoxifen on well-established surrogate biomarkers of chemopreventive efficacy; 2) Establish the safety and tolerability of low-dose tamoxifen in this population; and, as an exploratory aim, 3) Examine the modifying effect of several well-defined demographic and clinical characteristics associated with radiation-related BC risk on the risk:benefit ratio from this intervention. Eligible subjects who provide informed consent will be randomized to 5 mg per day of tamoxifen versus placebo for two years. Outcomes will include several surrogate biomarkers of efficacy, including mammographic breast density (MBD, primary endpoint), breast cytomorphologic and proliferation measures, and insulin growth factors. Subjects will be carefully followed for safety and tolerability using patient-reported outcomes as well as lipid profiles, clotting factors, and markers of bone turnover as objective endpoints. Risk modifiers that will be examined include age, menopausal status, prior hormone use, body mass index, personal history of benign breast disease, and family history of cancer, as well as chest radiation dose, age at exposure, and latency from chest radiation. A sample size of 127 per arm will be able to detect a 20% reduction in MBD with low-dose tamoxifen relative to placebo with 80% power. We have identified over 900 potentially eligible subjects within our consortium of five institutions that have well-developed infrastructure to follow childhood cancer survivors long-term, thus demonstrating that we will have a sufficiently sized pool to draw the eligible patient population from and complete the study. At completion of this study, we hope to identify a well-tolerated risk reduction option for HL survivors that are at high risk for developing BC. Low-dose Tamoxifen in Hodgkin Lymphoma Survivors for Breast Cancer Risk Reduction Public Health Relevance: Survival from Hodgkin lymphoma (HL) is excellent, but chest radiotherapy (RT) has been a cornerstone of treatment, and women with HL exposed to chest RT when they are young have a 20- to 55-fold increased risk of developing breast cancer (BC). Tamoxifen reduces the risk of BC by 50%, but at the cost of some undesirable side effects, while more recent studies suggest that lower dose tamoxifen may be similarly efficacious in reducing BC risk with fewer side effects. We believe that tamoxifen administered at 5 mg daily would be an ideal non-surgical risk reduction intervention for female HL survivors exposed to chest RT at high risk for BC; therefore, we plan to test this hypothesis in a Phase IIb clinical trial.